EP0999852A1 - Compositions de vaccins huile-dans-eau - Google Patents

Compositions de vaccins huile-dans-eau

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Publication number
EP0999852A1
EP0999852A1 EP98933600A EP98933600A EP0999852A1 EP 0999852 A1 EP0999852 A1 EP 0999852A1 EP 98933600 A EP98933600 A EP 98933600A EP 98933600 A EP98933600 A EP 98933600A EP 0999852 A1 EP0999852 A1 EP 0999852A1
Authority
EP
European Patent Office
Prior art keywords
oil
water emulsion
adjuvant composition
triglyceride
antigen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98933600A
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German (de)
English (en)
Inventor
Nathalie-SmithKline Beecham Biolog. S.A. GARCON
Patricia Marie Christine Aline Françoise MOMIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline Biologicals SA
Original Assignee
SmithKline Beecham Biologicals SA
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Filing date
Publication date
Application filed by SmithKline Beecham Biologicals SA filed Critical SmithKline Beecham Biologicals SA
Publication of EP0999852A1 publication Critical patent/EP0999852A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to an improvement in an oil in water vaccine composition.
  • the present invention relates to a vaccine adjuvant formulation based on oil in water emulsion comprising a metabolisable oil squalene, ⁇ -tocopherol, TWEEN 80, which has been improved by the inclusion of a triglyceride, further, these vaccine adjuvants can optionally comprise an immunologically active fraction of QuilA (preferably QS21) and 3D-MPL.
  • Tricaprylin C 2 H 50 O 6
  • QS21 is a HPLC purified non-toxic fraction of a saponin from the bark of the South American tree Quillaja Saponaria Molina, and the method of its production is disclosed (also known as QA21) in the US patent No. 5,057,540.
  • 3 De-O-acylated monophosphoryl lipid A is a well known adjuvant manufactured by Ribi Immunochem, Montana. Chemically it is supplied as a mixture of 3 De-O-acylated monophosphoryl lipid A with either 4, 5, or 6 acylated chains. Alternatively, it can be manufactured according to the disclosure of GB 2,220,21 1 (Ribi).
  • a preferred form of 3 De-O-acylated monophosphoryl lipid A and its method of manufacture is disclosed in International Patent Application No. 92/116556.
  • Oil in water emulsions per se are well known in the art, and have been suggested to be useful as adjuvant compositions (EPO 399843).
  • a vaccine antigen does not enter into, and replicate within, the cytoplasm of the host cell, then it will enter the Th2 pathway and ultimately be presented on the surface of the cell associated with a MHC class II molecule. This alternative route generally results in T- helper responses and antigen specific antibody responses.
  • Thl-type cytokines eg. IFN- ⁇ and IL-2.
  • IFN- ⁇ secretion is associated with protective responses against intracellular pathogens, including parasites, bacteria and viruses.
  • Activation of leucocytes by IFN- ⁇ enhances killing of intracellular pathogens and increases expression of Fc receptors.
  • Direct cytotoxicity may also occur, especially in synergism with lymphotoxin (another product of TH1 cells).
  • IFN- ⁇ is also both an inducer and a product of NK cells, which are major innate effectors of protection.
  • TH1 type responses either through IFN- ⁇ or other mechanisms, provide preferential help for murine IgG2a immunoglobulin isotypes.
  • the larger particle stands out amongst the preparations as being the best size of droplet to induce immune responses, it suffers from the disadvantage of lack of stability.
  • the emulsion breaks down. Indeed, in order to attain a uniform vaccine preparation, the emulsion has to be produced immediately prior to use.
  • the present invention solves the problem of emulsion instability and retains the preferred diameter of the large oil in water droplets for optimal adjuvanticity. This has been achieved by the formulation of the oil in water emulsion in the presence of a triglyceride oil.
  • the oil in water emulsions of the present invention are stable.
  • the oil droplet diameter remains at a relatively constant level over a prolonged period of time.
  • the emulsions of the present invention will not cream, or separate into two phases, for a period of over 1 year at 4°C, and most preferably over 2 years.
  • a vaccine or pharmaceutical formulation comprising an antigen in conjunction with 3 De-O-acylated monophosphoryl lipid A, QS21, a triglyceride and an oil in water emulsion, wherein the triglyceride may be tricaprylin and the oil in water emulsion comprises a metabolisible oil (such as squalene), ⁇ -tocopherol and TWEEN 80.
  • a metabolisible oil such as squalene
  • ⁇ -tocopherol such as squalene
  • TWEEN 80 a metabolisible oil
  • Such a formulation is suitable for a broad range of monovalent or polyvalent vaccines. Additionally the oil in water emulsion may contain span 85.
  • a preferred form of 3 De-O-acylated monophosphoryl lipid A is disclosed in International patent application published under No.
  • the size range of oil droplet found within the stable oil in water emulsion is the important aspect of this invention. It is envisaged that embodiments of this invention will be in the range of substantially 300-600nm, preferably substantially around 350-550nm in diameter, and most preferably substantially 450-500nm in diameter as measured by photon correlation spectroscopy. Although many of the examples described herein have droplet sizes of substantially 500nm it will be appreciated by the man skilled in the art that the invention is applicable to oil in water emulsions wherein the oil droplets are greater than substantially 500nm in diameter, thus oil droplets may have an average droplet size of 600nm or greater.
  • the oil droplet diameter may be within the range of substantially 500-600nm.
  • the definition of substantially in relation to this invention is greater than 80% of the oil droplets by number being within the stated ranges, preferably greater than 90%, and most preferably greater than 95%.
  • the oil phase of the emulsion system has to comprise a metabolisable oil.
  • metabolisable oil is well known in the art. Metabolisable can be defined as "being capable of being transformed by metabolism" (Dorland's Illustrated Medical Dictionary, W.B. Sanders Company, 25th edition (1974)).
  • the oil may be any vegetable oil, fish oil, animal oil or synthetic oil, which is not toxic to the recipient and is capable of being transformed by metabolism.
  • Nuts, seeds, and grains are common sources of vegetable oils. Synthetic oils are also part of this invention and can include commercially available oils such as NEOBEE® and others.
  • Squalene (2,6,10,15, 19,23-Hexamethyl- 2,6,10,14,18,22-tetracosahexaene) is an unsaturated oil which is found in large quantities in shark-liver oil, and in lower quantities in olive oil, wheat germ oil, rice bran oil, and yeast, and is a particularly preferred oil for use in this invention. Squalene is a metabolisable oil virtue of the fact that it is an intermediate in the biosynthesis of cholesterol (Merck index, 10th Edition, entry no.8619).
  • the oil in water emulsion may be utilised on its own or with other adjuvants or immunostimulants and therefore an important embodiment of the invention is an oil in water formulation comprising squalene or another metabolisable oil, a triglyceride, such as tricaprylin, ⁇ -tocopherol, and polyoxyethylene sorbitan monooleate (TWEEN 80TM).
  • the oil in water emulsion may also contain span 85 and/or Lecithin.
  • the present invention comprises an adjuvant composition comprising an oil in water emulsion consisting of squalene, TWEEN80TM, ⁇ -tocopherol, wherein the oil droplets within the emulsion have an average diameter of substantially 300-600nm.
  • the present invention also provides for a vaccine comprising an oil in water emulsion consisting of squalene, TWEEN80TM, ⁇ -tocopherol, wherein the oil droplets within the emulsion have an average diameter of substantially 300-600nm, and an antigen or antigenic preparation.
  • the adjuvant composition, or vaccine composition, as described above further comprises QS21 and 3D-MPL.
  • the vaccine formulations of the present invention contain an antigen or antigenic composition capable of eliciting an immune response against a human pathogen, which antigen or antigenic composition is derived from HIV-1, (such as tat, nef, gpl20 or gpl60), human herpes viruses, such as gD or derivatives thereof or
  • Immediate Early protein such as ICP27 from HSV1 or HSV2, cytomegalovirus ((esp Human)(such as gB or derivatives thereof), Rotavirus (including live-attenuated viruses), Epstein Barr virus (such as gp350 or derivatives thereof), Varicella Zoster Virus (such as gpl, II and IE63), or from a hepatitis virus such as hepatitis B virus (for example Hepatitis B Surface antigen or a derivative thereof), hepatitis A virus, hepatitis C virus and hepatitis E virus, or from other viral pathogens, such as paramyxo viruses: Respiratory Syncytial virus (such as F and G proteins or derivatives thereof), parainfluenza virus, measles virus, mumps virus, human papilloma viruses (for example HPV6, 11, 16, 18, such as LI, L2, E6 or E7 antigens), flaviviruses (e.g.
  • Neisseria spp including ⁇ r . gonorrhea and N. meningitidis (for example capsular polysaccharides and conjugates thereof, transferrin-binding proteins, lactoferrin binding proteins, PilC, adhesins); Streptococcus spp, including S. pneumoniae (for example capsular polysaccharides and conjugates thereof, PsaA, PspA, streptolysin, choline-binding proteins), S.
  • Neisseria spp including ⁇ r . gonorrhea and N. meningitidis (for example capsular polysaccharides and conjugates thereof, transferrin-binding proteins, lactoferrin binding proteins, PilC, adhesins); Streptococcus spp, including S. pneumoniae (for example capsular polysaccharides and conjugates thereof, PsaA, PspA, streptolysin, choline-binding proteins), S.
  • pyogenes for example M proteins or fragments thereof, C5A protease, lipoteichoic acids), S. agalactiae, S. mutans; Haemophilus spp, including H. influenzae type B (for example PRP and conjugates thereof), non typeable H. influenzae (for example OMP26, high molecular weight adhesins, P5, P6, lipoprotein D), H. ducreyi; Moraxella spp, including M catarrhalis, also known as Branhamella catarrhalis (for example high and low molecular weight adhesins and invasins); Bordetella spp, including B.
  • H. influenzae type B for example PRP and conjugates thereof
  • non typeable H. influenzae for example OMP26, high molecular weight adhesins, P5, P6, lipoprotein D
  • Moraxella spp including M catarrhalis, also known as Branhamella catarrhalis (for example high
  • pertussis for example pertactin, pertussis toxin or derivatives thereof, filamenteous hemagglutinin, adenylate cyclase, fimbriae), B. parapertussis and B. bronchiseptica; Mycobacterium spp., including M. tuberculosis (for example ESAT6, Antigen 85A, -B or -C), M. bovis, M. leprae, M. avium, M. paratuberculosis, M. smegmatis; Legionella spp, including L. pneumophila; Escherichia spp, including enterotoxic E.
  • M. tuberculosis for example ESAT6, Antigen 85A, -B or -C
  • M. bovis for example ESAT6, Antigen 85A, -B or -C
  • M. bovis for example ESAT6, Antigen 85A, -B or -C
  • M. bovis for example ESAT6,
  • coli for example colonization factors, heat-labile toxin or derivatives thereof, heat-stable toxin or derivatives thereof), enterohemorragic E. coli, enteropathogenic E. coli (for example shiga toxin-like toxin or derivatives thereof); Vibrio spp, including V. cholera (for example cholera toxin or derivatives thereof); Shigella spp, including S. sonnei, S. dysenteriae, S. flexnerii; Yersinia spp, including Y. enterocolitica (for example a Yop protein) , Y. pestis, Y. pseudotuberculosis; Campylobacter spp, including C.
  • V. cholera for example cholera toxin or derivatives thereof
  • Shigella spp including S. sonnei, S. dysenteriae, S. flexnerii
  • Yersinia spp including Y. enterocolitica (for example
  • jejuni for example toxins, adhesins and invasins
  • C. coli Salmonella spp, including S. typhi, S. paratyphi, S. choleraesuis, S. enter itidis
  • Lister ia spp. including L. monocytogenes
  • Helicobacter spp including H. pylori (for example urease, catalase, vacuolating toxin); Pseudomonas spp, including P. aeruginosa; Staphylococcus spp., including S. aureus, S. epidermidis; Enter ococcus spp., including E. faecalis, E.
  • Clostridium spp. including C. tetani (for example tetanus toxin and derivative thereof), C. botulinum (for example botulinum toxin and derivative thereof), C. difficile (for example clostridium toxins A or B and derivatives thereof); Bacillus spp., including B. anthracis (for example botulinum toxin and derivatives thereof); Corynebacterium spp., including C. diphtheriae (for example diphtheria toxin and derivatives thereof); Borrelia spp., including B. burgdorferi (for example OspA, OspC, DbpA, DbpB), B.
  • garinii for example OspA, OspC, DbpA, DbpB
  • R. afzelii for example OspA, OspC, DbpA, DbpB
  • R. andersonii for example OspA, OspC, DbpA, DbpB
  • R. hermsii for example E. equi and the agent of the Human Granulocytic Ehrlichiosis
  • Rickettsia spp including R. rickettsii
  • Chlamydia spp. including C. trachomatis (for example MOMP, heparin- binding proteins), C.
  • pneumoniae for example MOMP, heparin-binding proteins), C. psittaci; Leptospira spp., including L. interrogans; Treponema spp., including T. pallidum (for example the rare outer membrane proteins), T. denticola, T. hyodysenteriae; or derived from parasites such as Plasmodium spp., including R. falciparum; Toxoplasma spp., including T. gondii (for example SAG2, SAG3, Tg34); Entamoeba spp., including E. histolytica; Babesia spp., including R. microti;
  • Trypanosoma spp. including T. cruzi; Giardia spp., including G. lamblia; Leshmania spp., including L. major; Pneumocystis spp., including R. carinii; Trichomonas spp., including T. vaginalis; Schisostoma spp., including S. mansoni, or derived from yeast such as Candida spp., including C. albicans; Cryptococcus spp., including C. neoformans.
  • the vaccine formulation of the invention comprises the HIV-1 antigen, gpl20, especially when expressed in CHO cells.
  • the vaccine formulation of the invention comprises gD2t as hereinabove defined.
  • vaccines containing the claimed adjuvant comprise the HPV viruses considered to be responsible for genital warts, ( ⁇ PV 6 or HPV 11 and others), and the HPV viruses responsible for cervical cancer (HPV 16, HPV 18 and others).
  • Rarticularly preferred forms of vaccine comprise LI particles or capsomers, and fusion proteins comprising one or more antigens selected from the HPV 6 and HPV 1 1 proteins E6, E7, LI, and L2.
  • the most preferred forms of fusion protein are: L2E7 as disclosed in GB 95 15478.7, and proteinD(l/3)-E7 disclosed in GB 9717953.5.
  • Vaccines of the present invention further comprise antigens derived from parasites that cause Malaria.
  • RTS is a hybrid protein comprising substantially all the C-terminal portion of the circumsporozoite (CS) protein of P. falciparum linked via four amino acids of the preS2 portion of Hepatitis B surface antigen to the surface (S) antigen of hepatitis B virus. It's full structure is disclosed in the International Patent Application No. PCT/EP92/02591, published under Number WO 93/10152 claiming priority from UK patent application No.9124390.7. When expressed in yeast RTS is produced as a lipoprotein particle, and when it is co-expressed with the S antigen from HBV it produces a mixed particle known as RTS,S.
  • TRAP antigens are described in the
  • a preferred embodiment of the present invention is a Malaria vaccine wherein the antigenic preparation comprises a combination of the RTS,S and TRAP antigens.
  • Other plasmodia antigens that are likely candidates to be components of a multistage Malaria vaccine are P. faciparum MSP 1 , AMA 1 , MSP3 , EB A, GLURP, RAP 1 , RAP2,
  • the formulations may also contain an anti-tumour antigen and be useful for the immunotherapeutic treatment cancers.
  • the adjuvant formulation finds utility with tumour rejection antigens such as those for prostrate, breast, colorectal, lung, pancreatic, renal or melanoma cancers.
  • Exemplary antigens include MAGE 1 and MAGE 3 or other MAGE antigens for the treatment of melanoma, PRAME, BAGE or GAGE (Robbins and Kawakami, 1996, Current Opinions in Immunology 8, pps 628- 636; Van den Eynde et al., International Journal of Clinical & Laboratory Research (submitted 1997); Correale et al. (1997), Journal of the National Cancer Institute 89, p293. Indeed these antigens are expressed in a wide range of tumour types such as melanoma, lung carcinoma, sarcoma and bladder carcinoma.
  • Tumor-Specific antigens are suitable for use with adjuvant of the present invention and include, but are not restricted to Prostate specific antigen (PSA) or Her-2/neu, KSA (GA733), MUC-1 and carcinoembryonic antigen (CEA). Accordingly in one aspect of the present invention there is provided a vaccine comprising an adjuvant composition according to the invention and a tumour rejection antigen.
  • PSA Prostate specific antigen
  • KSA Her-2/neu
  • CEA carcinoembryonic antigen
  • compositions of the present invention are a vaccine composition comprising the hormone antigen gonadotropin releasing hormone (GnRH).
  • GnRH gonadotropin releasing hormone
  • Immunogenic conjugates of this antigen are disclosed in WO 95/20600, EP 0117934, US 4,302,386 and US 5,006,334.
  • Such vaccines are especially useful in the treatment of cancer.
  • compositions of the present invention will be used to formulate vaccines containing antigens derived from Borrelia sp.
  • antigens may include nucleic acid, pathogen derived antigen or antigenic preparations, recombinantly produced protein or peptides, and chimeric fusion proteins.
  • the antigen is OspA.
  • the OspA may be a full mature protein in a lipidated form virtue of the host cell (E.Coli) termed (Lipo-OspA) or a non-lipidated derivative.
  • Such non-lipidated derivatives include the non-lipidated NSl-OspA fusion protein which has the first 81 N- terminal amino acids of the non- structural protein (NS 1) of the influenza virus, and the complete OspA protein, and another, MDP-OspA is a non-lipidated form of OspA carrying 3 additional N-terminal amino acids.
  • Vaccines of the present invention may be used for the prophylaxis or therapy of allergy.
  • Such vaccines would comprise allergen specific (for example Der pi) and allergen non- specific antigens (for example the stanworth decapeptide).
  • a vaccine preparation of the present invention may be used to protect or treat a mammal susceptible to, or suffering from a disease, by means of administering said vaccine via a mucosal route, for example, an oral or intranasal route; or by a parenteral route, for example an intramuscular route.
  • a mucosal route for example, an oral or intranasal route
  • a parenteral route for example an intramuscular route.
  • the ratio of tricapryli metabolisable oil, preferably squalene would be in the order of 1 : 10 to 10:1, preferably from 1 :5 to 5:1.
  • the ratio of QS21 : 3D-MPL will typically be in the order of 1 : 10 to 10 : 1; preferably 1 : 5 to 5 : 1 and often substantially 1 : 1.
  • the preferred range for optimal synergy is 2.5:1 to 1 :1 3D-MPL: QS21.
  • QS21 and 3D MPL will be present in a vaccine in the range 1 ⁇ g - 1000 ⁇ g, preferably 10 ⁇ g - 500 ⁇ g, more preferably 20-200 ⁇ g per dose, more preferably 20-100 ⁇ g per dose, and most preferably 10-50 ⁇ g per dose.
  • the oil in water will comprise from 2 to 10% squalene, from 2 to 10% ⁇ -tocopherol and from 0.3 to 3% TWEEN 80.
  • the ratio of squalene: ⁇ -tocopherol is equal or less than 1 as this provides a more stable emulsion.
  • Span 85 may also be present at a level of 1%. In some cases it may be advantageous that the vaccines of the present invention will further contain another stabiliser.
  • Vaccine preparation is generally described in New Trends and Developments in Vaccines, edited by Voller et al., University Park Press, Baltimore, Maryland, U.S.A. 1978.
  • Encapsulation within liposomes is described, for example, by Fullerton, U.S. Patent 4,235,877.
  • Conjugation of proteins to macromolecules is disclosed, for example, by Likhite, U.S. Patent 4,372,945 and by Armor et al., U.S. Patent 4,474,757.
  • each vaccine dose is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccinees. Such amount will vary depending upon which specific immunogen is employed and how it is presented. Generally, it is expected that each dose will comprise 1-1000 ⁇ g of protein, preferably 2-100 ⁇ g, most preferably 4-40 ⁇ g. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of appropriate immune responses in subjects. Following an initial vaccination, subjects may receive one or several booster immunisation adequately spaced.
  • the method of producing the oil in water emulsions described in the examples comprises the mixing the oil phase with a PBS/TWEEN80TM solution followed by homogenisation using a homogenizer, it would be clear to a man skilled in the art that a method comprising passing the mixture twice through a syringe needle would be suitable for homogenising small volumes of liquid.
  • the emulsification process in microfluidiser MHOS microfluidics machine, maximum of 50 passes, for a period of 2 minutes at maximum pressure imput of 6 bar (output pressure of about 850 bar)
  • This adaptation could be achieved by routine experimentation comprising the measurement of the resultant emulsion until a preparation was achieved with oil droplets of the required diameter.
  • the formulations of the present invention maybe used for both prophylactic and therapeutic purposes.
  • Also provided by the present invention is a method for stabilising an oil in water emulsion, said oil in water emulsion not being stable for a period of two years, comprising the addition of a triglyceride to the oil phase.
  • a triglyceride used in this method is trycaprylin.
  • oil in water emulsion adjuvants composed of an organic phase ( ⁇ -tocopherol, tricaprylin and squalene), an aqueous phase (PBS), and one or several emulsifiers (including TWEEN 80), are manufactured in a similar manner to that described in WO
  • TWEEN 80 is dissolved in phosphate buffered saline (PBS) to give a 0.4% solution in the PBS.
  • PBS phosphate buffered saline
  • a homogenizer ultrathurax type
  • the preparation is emulsified by passes through a microfluidiser (MHOS microfluidics machine).
  • MHOS microfluidics machine The emulsion undergoes a maximum of 50 passes, for a period of 2 minutes at maximum pressure imput of 6 bar (output pressure of about 850 bar).
  • the resulting oil droplets have a size of approximately 300-600 nm.
  • Table 1 Formulation of SB 26 emulsions optionally containing tricaprylin, for use in stability assays.
  • Example 2 Adjuvant stability 1.
  • the stability of the adjuvant preparations described in the example above was investigated over varying periods of time and storage conditions.
  • the initial size of the adjuvant preparations were compared with that found after storage over 8 hours at 75 °C, 1 month being stored at either 37 or 45 °C, 12 months being stored at 4°C, or after accelerated decay test comprising centrifugation at 3000xg.
  • the average size of the oil in water droplets were measured by photon correlation spectroscopy and expressed as count rate (CR), intensity distribution, mass distribution, and average size of particle (table 5).
  • Example 4 Vaccination studies in mice using the stable oil in water emulsion adjuvant Groups of Balb/C mice were immunised intramuscularly on three occasions (days 0, 14, 28) with the experimental vaccines comprising the malaria antigen RTS,S, HIV gpl20, oil in water emulsion, and optionally tricaprylin.
  • SB26 oil in water emulsions that were used were prepared according to the techniques described in WO 95/17210. These emulsions had a mean oil droplet diameter of 500nm and had a lifetime of 1 month.
  • SB62 150nm - stable for more than 2 years was also made according to the techniques described in WO 95/17210, and were compared to ensure that the resultant immune response was not impeded by the addition of tricaprylin.
  • SB26T1 and SB26T2.5 have a mean particle size of about 500nm and are stable for over 2 years.
  • 3 De-O-acylated monophosphoryl lipid A (3D-MPL) is known from GB2220
  • QS21 is a HPLC purified non toxic fraction of a saponin from the bark of the
  • Example 6 Vaccination studies in rhesus monkeys using the stable oil in water emulsion adjuvant Groups of 5 rhesus monkeys were immunised on three occasions (days 0, 28, and 84) with the vaccine formulations as given in table 4.
  • the antigens RTS,S and gpl20 were produced as previously described.
  • the vaccines were administered intramuscularly as a bolus injection into the posterior part of the left (gpl20) or the right (RTS,S) leg. The final volume of each vaccine was 0.5ml.
  • Blood samples were taken 14 days after each vaccination and were assayed for antigen specific humoral and cell mediated responses.
  • PBMC monkey peripheral blood mononuclear cells

Abstract

L'invention concerne des émulsions améliorées stables huile-dans-eau, dont le diamètre de la gouttelette d'huile est sensiblement de 300-600nm et comprend des triglycérides, ainsi que leur utilisation en tant qu'adjuvants de vaccins.
EP98933600A 1997-06-11 1998-06-03 Compositions de vaccins huile-dans-eau Withdrawn EP0999852A1 (fr)

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GBGB9711990.3A GB9711990D0 (en) 1997-06-11 1997-06-11 Vaccine
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PCT/EP1998/003479 WO1998056414A1 (fr) 1997-06-11 1998-06-03 Compositions de vaccins huile-dans-eau

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CN1260723A (zh) 2000-07-19
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NO996133L (no) 2000-01-26
TR199903048T2 (xx) 2000-08-21
WO1998056414A1 (fr) 1998-12-17
PL337488A1 (en) 2000-08-28
GB9711990D0 (en) 1997-08-06
AU8336598A (en) 1998-12-30
AU728759B2 (en) 2001-01-18
NO996133D0 (no) 1999-12-10
HUP0004001A2 (en) 2001-03-28
CA2293444A1 (fr) 1998-12-17
ZA984969B (en) 1999-12-09
BR9810614A (pt) 2000-09-12
IL133126A0 (en) 2001-03-19
KR20010013644A (ko) 2001-02-26
JP2002504106A (ja) 2002-02-05

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